ALKBH5-mediated m6A modification of circFOXP1 promotes gastric cancer progression by regulating SOX4 expression and sponging miR-338-3p.

Circular RNAs (circRNAs) have recently been suggested as potential functional modulators of cellular physiology processes in gastric cancer (GC). In this study, we demonstrated that circFOXP1 was more highly expressed in GC tissues. High circFOXP1 expression was positively associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis in patients with GC. Cox multivariate analysis revealed that higher circFOXP1 expression was an independent risk factor for disease-free survival (DFS) and overall survival (OS) in GC patients. Functional studies showed that increased circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, the knockdown of circFOXP1 inhibited tumor growth. Mechanistically, we observed ALKBH5-mediated m6A modification of circFOXP1 and circFOXP1 promoted GC progression by regulating SOX4 expression and sponging miR-338-3p in GC cells. Thus, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for GC.

Turtle peptide and its derivative peptide ameliorated DSS-induced ulcerative colitis by inhibiting inflammation and modulating the composition of the gut microbiota.

Ulcerative colitis (UC) is a recurrent intestinal disease with an increasing incidence worldwide that seriously affects the life of patients. Turtle peptide (TP) is a bioactive peptide extracted from turtles that has anti-inflammatory, antioxidant and anti-aging properties. However, studies investigating the effect of TP on the progression of UC are lacking. The aim of this study was to investigate effects and underlying mechanisms of TP and its derivative peptide GPAGPIGPV (GP-9) in alleviating UC in mice. The results showed that 500 mg/kg TP treatment significantly ameliorated colitis symptoms and oxidative stress in UC mice. TP alleviated intestinal barrier damage in UC mice by promoting mucosal repair and increasing the expression of tight junction proteins (ZO1, occludin and claudin-1). TP also modulated the composition of the gut microbiota by increasing the abundance of the beneficial bacteria Anaerotignum, Prevotellaceae_UCG-001, Alistipes, and Lachno-spiraceae_NK4A136_group and decreasing the abundance of the harmful bacteria Prevotella_9 and Parasutterella. Furthermore, we characterized the peptide composition of TP and found that GP-9 ameliorated the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, TP and its derivative peptides ameliorated DSS-induced ulcerative colitis by inhibiting the expression of inflammatory factors and modulating the composition of the intestinal microbiota; this study provides a theoretical basis for the application of TP and its derivative peptides for their anti-inflammatory activity.

Stem moisture content prediction model for Larix olgensis based on beta regression.

To investigate the longitudinal variation patterns of sapwood, heartwood, bark and stem moisture content along the trunk of artificial Larix olgensis, we constructed mixed effect models of moisture content based on beta regression by combining the effects of sampling plot and sample trees. We used two sampling schemes to calibrate the model, without limiting the relative height (Scheme Ⅰ) and with a limiting height of less than 2 m (Scheme II). The results showed that sapwood and stem moisture content increased gradually along the trunk, heartwood moisture content decreased slightly and then increased along the trunk, and bark moisture content increased along the trunk and then levelled off before increasing. Relative height, height to crown base, stand area at breast height per hectare, age, and stand dominant height were main factors driving moisture content of L. olgensis. Scheme Ⅰ showed the stable prediction accuracy when randomly sampling moisture content measurements from 2-3 discs to calibrate the model, with the mean absolute percentage error (MAPE) of up to 7.2% for stem moisture content (randomly selected 2 discs), and the MAPE of up to 7.4%, 10.5% and 10.5% for sapwood, heartwood and bark moisture content (randomly selected 3 discs), respectively. Scheme Ⅱ was appropriate when sampling moisture content measurements from discs of 1.3 and 2 m height and the MAPE of sapwood, heartwood, bark and stem moisture content reached 7.8%, 11.0%, 10.4% and 7.1%, respectively. The prediction accuracies of all mixed effect beta regression models were better than the base model. The two-level mixed effect beta regression models, considering both plot effect and tree effect, would be suitable for predicting moisture content of each part of L. olgensis well.

Highly sensitive dual-function sensor for refractive index and temperature using D-shaped microchannel photonic crystal fiber.

An innovative ultra-sensitive, dual-functional sensor employing a D-shaped microchannel photonic crystal fiber (PCF) for refractive index (RI) and temperature measurements is proposed and comprehensively investigated. Its high-sensitivity is achieved through the incorporation of gold (Au) and magnesium fluoride (MgF2) as plasmonic materials in the micro-rectangular channel. This configuration significantly enhances the interaction between the surface plasmon polaritons (SPPs) field and y-polarized evanescent field on external surfaces. Additionally, the integration of a temperature-sensitive fluid within the sensor allows for precise detection of temperature changes. Our simulations demonstrate a broad detection spectrum, covering RI values from 1.27 to 1.43 and temperatures ranging from 45°C to 100°C. The sensor achieves peak sensitivities of 31800nm/RIU for RI and 49 nm/°C for temperature. Besides, the sensor only has a cladding consisting of three air holes to enhance coupling and reduce the difficulty of preparation. Importantly, the sensor's performance remains robust against minor structural alterations in the PCF, indicating high fault tolerance. Given its high sensitivity, extensive detection range, and strong fabrication stability, this PCF-SPR sensor offers significant potential for applications in biochemical sensing and environmental monitoring.

Transforming outcome expectations into retention among hospital nurses: A cross-sectional study.

AIM: To examine the main effects and interaction effects of outcome expectations (e.g., anticipated satisfactory salary and benefits), nurse identity (a sense of membership in the nursing profession), and information-access efficiency of the electronic medical record system (how the system enables nurses to quickly retrieve the needed information) on nurses' retention. DESIGN: This study uses a cross-sectional survey and adopts proportionate random sampling to recruit a representative sample of nurses of a medical centre in Taiwan. METHODS: This study successfully obtained completed questionnaires from 430 nurses during December 2021 to January 2022. Data are analysed by using hierarchical regressions. RESULTS: Positive outcome expectations and identification as a member in the nursing profession are associated with retention. Information-access efficiency strengthens the link between outcome expectations and retention, while nurse identity weakens this link. CONCLUSION: Outcome expectations can help retain nurses, particularly those who perceive high levels of information-access efficiency and possess weak nurse identity. That is, outcome expectations have a complementary role with nurse identity in retaining nurses. IMPLICATIONS FOR THE PROFESSION: Nurse managers should devise means to build positive outcome expectations for nurses. In addition, either strengthening nurses' identification with the nursing profession or improving the information-access efficiency of the electronic medical system may also help retain nurses. IMPACT: This study examined how to transform outcome expectation to nurse retention, offering nurse managers to devise new means to retain nurses. REPORTING METHOD: STROBE statement was chosen as EQUATOR checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Height-diameter model of broad-leaved mixed forest based on species classification in Maoershan, Northeast China.

The complex stand structure and high species diversity of natural forests pose great challenges for analyzing stand growth and formulating reasonable plans for forest management. The height-diameter relationship is of great significance for predicting stand growth and formulating forest management measures. Based on survey data of 48 broad-leaved mixed forest plots in Maoershan, we classified 23 tree species into four groups based on species structure, growth characteristics and bionomics. We established a generalized model including stand, tree competition, species mixing and species diversity variables by reparameterization method, and a two-level mixed effect model of plot and tree species group. We tested the prediction ability of the model by leave-one-out cross-validation method. The results showed that the Ratkowsky (1990) model was the optimal basic model. The introduction of dominant height, basal area of trees larger than the object tree, basal area proportion of each species, and Shannon index could better explain the height-diameter relationship of broad-leaved mixed forest in Maoershan. The introduction of the mixed effect model of plot and tree species group could significantly improve the prediction accuracy of the model, with a Ra2 of 0.83. Under the same gradient of environmental factors, intolerant tree species exhibited higher tree heights than shade-tolerant tree species. In this study, we used the constructed tree height-diameter model to analyze the effects of species mixing and tree functional traits on tree height, which provided a theoretical basis for accurately predicting height of different tree species and analyzing the growth relationships in broadleaved mixed forests.

Halide Superionic Conductors with Non-Close-Packed Anion Frameworks.

Halide superionic conductors (SICs) are drawing significant research attention for their potential applications in all-solid-state batteries. A key challenge in developing such SICs is to explore and design halide structural frameworks that enable rapid ion movement. In this work, we show that the close-packed anion frameworks shared by traditional halide ionic conductors face intrinsic limitations in fast ion conduction, regardless of structural regulation. Beyond the close-packed anion frameworks, we identify that the non-close-packed anion frameworks have great potential to achieve superionic conductivity. Notably, we unravel that the non-close-packed UCl3-type framework exhibit superionic conductivity for a diverse range of carrier ions, including Li+, Na+, K+, and Ag+, which are validated through both ab initio molecular dynamics simulations and experimental measurements. We elucidate that the remarkable ionic conductivity observed in the UCl3-type framework structure stems from its significantly more distorted site and larger diffusion channel than its close-packed counterparts. By employing the non-close-packed anion framework as the key feature for high-throughput computational screening, we also identify LiGaCl3 as a promising candidate for halide SICs. These discoveries provide crucial insights for the exploration and design of novel halide SICs.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

Perforated gastric ulcer causing mediastinal emphysema: A case report.

BACKGROUND: Mediastinal emphysema is a condition in which air enters the mediastinum between the connective tissue spaces within the pleura for a variety of reasons. It can be spontaneous or secondary to chest trauma, esophageal perforation, medically induced factors, etc. Its common symptoms are chest pain, tightness in the chest, and respiratory distress. Most mediastinal emphysema patients have mild symptoms, but severe mediastinal emphysema can cause respiratory and circulatory failure, resulting in serious consequences. CASE SUMMARY: A 75-year-old man, living alone, presented with sudden onset of severe epigastric pain with chest tightness after drinking alcohol. Due to the remoteness of his residence and lack of neighbors, the patient was found by his nephew and brought to the hospital the next morning after the disease onset. Computed tomography (CT) showed free gas in the abdominal cavity, mediastinal emphysema, and subcutaneous pneumothorax. Upper gastrointestinal angiography showed that the esophageal mucosa was intact and the gastric antrum was perforated. Therefore, we chose to perform open gastric perforation repair on the patient under thoracic epidural anesthesia combined with intravenous anesthesia. An operative incision of the muscle layer of the patient's abdominal wall was made, and a large amount of subperitoneal gas was revealed. And a continued incision of the peritoneum revealed the presence of a perforation of approximately 0.5 cm in the gastric antrum, which we repaired after pathological examination. Postoperatively, the patient received high-flow oxygen and cough exercises. Chest CT was performed on the first and sixth postoperative days, and the mediastinal and subcutaneous gas was gradually reduced. CONCLUSION: After gastric perforation, a large amount of free gas in the abdominal cavity can reach the mediastinum through the loose connective tissue at the esophageal hiatus of the diaphragm, and upper gastrointestinal angiography can clarify the site of perforation. In patients with mediastinal emphysema, open surgery avoids the elevation of the diaphragm caused by pneumoperitoneum compared to laparoscopic surgery and avoids increasing the mediastinal pressure. In addition, thoracic epidural anesthesia combined with intravenous anesthesia also avoids pressure on the mediastinum from mechanical ventilation.

A chromosome-level genome assembly of the forestry pest Coronaproctus castanopsis.

As an important forestry pest, Coronaproctus castanopsis (Monophlebidae) has caused serious damage to the globally valuable Gutianshan ecosystem, China. In this study, we assembled the first chromosome-level genome of the female specimen of C. castanopsis by merging BGI reads, HiFi long reads and Hi-C data. The assembled genome size is 700.81 Mb, with a scaffold N50 size of 273.84 Mb and a contig N50 size of 12.37 Mb. Hi-C scaffolding assigned 98.32% (689.03 Mb) of C. Castanopsis genome to three chromosomes. The BUSCO analysis (n = 1,367) showed a completeness of 91.2%, comprising 89.2% of single-copy BUSCOs and 2.0% of multicopy BUSCOs. The mapping ratio of BGI, second-generation RNA, third-generation RNA and HiFi reads are 97.84%, 96.15%, 97.96%, and 99.33%, respectively. We also identified 64.97% (455.3 Mb) repetitive elements, 1,373 non-coding RNAs and 10,542 protein-coding genes. This study assembled a high-quality genome of C. castanopsis, which accumulated valuable molecular data for scale insects.

Early generation of a precursor CD8 T cell that can adapt to acute or chronic viral infection.

Virus specific PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells are essential for maintaining T cell responses during chronic infection and are also critical for PD-1 directed immunotherapy. In this study we have used the mouse model of chronic LCMV infection to examine when these virus specific stem-like CD8+ T cells are generated during the course of chronic infection and what is the role of antigen in maintaining the stem-like program. We found that these stem-like CD8+ T cells are generated early (day 5) during chronic infection and that antigen is essential for maintaining their stem-like program. This early generation of stem-like CD8+ T cells suggested that the fate commitment to this cell population was agnostic to the eventual outcome of infection and the immune system prepares a priori for a potential chronic infection. Indeed, we found that an identical virus specific stem-cell like CD8+ T cell population was also generated during acute LCMV infection but these cells were lost once the virus was cleared. To determine the fate of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells that are generated during both acute and chronic LCMV infection we set up two reciprocal adoptive transfer experiments. In the first experiment we transferred day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice and examined their differentiation after viral clearance. We found that these early stem-like CD8+ T cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. In the second experiment, we transferred day 5 stem-like cells from acutely infected mice into chronically infected mice and found that these CD8+ T cells could function like resource cells after transfer into a chronic environment by generating effector CD8+ T cells in both lymphoid and non-lymphoid tissues while also maintaining the number of stem-like CD8+ T cells. These findings provide insight into the generation and maintenance of virus specific stem-like CD8+ T cells that play a critical role in chronic viral infection. In particular, our study highlights the early generation of stem-like CD8+ T cells and their ability to adapt to either an acute or chronic infection. These findings are of broad significance since these novel stem-like CD8+ T cells play an important role in not only viral infections but also in cancer and autoimmunity.

Parental vaccine hesitancy and acceptance of a COVID-19 vaccine: An internet-based survey in the US and five Asian countries.

COVID-19 vaccination rates for children globally are relatively low. This study aimed to investigate parental vaccine hesitancy and parents' acceptance of a COVID-19 for their children for their children in the United States, China, Taiwan, India, Indonesia, and Malaysia.We analyzed data from an opt-in, internet-based cross-sectional study (n = 23,940). Parents were asked about their acceptance of a COVID-19 vaccine for their children, and if they would accept the vaccine with different risk and effectiveness profiles for themselves. Poisson regression was used to generate prevalence ratios (PR) of the relationship between vaccine acceptance for a child and vaccine profile, by country and waves and overall. Between August 2020 and June 2021, COVID-19 vaccine acceptance for children decreased in the United States (89% to 72%) and Taiwan (79% to 71%), increased in India (91% to 96%) and Malaysia (81% to 91%), and was stable in Indonesia (86%) and China (at 87%-90%). Vaccine risk and effectiveness profiles did not consistently affect parent's acceptance of a COVID-19 vaccine for their children. Instead, being not hesitant was a large driver of vaccine acceptance (PR: 1.24, 95% CI: 1.14, 1.36). Adolescent COVID-19 vaccination have already been established in many high and middle-income countries, but our study suggests that there is a movement of vaccine hesitancy which could impede the success of future pediatric and adolescent COVID-19 vaccination programs.

Chronic Low Back Pain and Sleep Disturbance in Adults in the US: The NHANES 2009-2010 Study.

BACKGROUND: Chronic low back pain (CLBP) is a significant health challenge with a high prevalence rate. Sleep disorders, which are prevalent among adults, have been linked with CLBP. However, the intricate relationship between sleep and pain adds complexity to our understanding of CLBP. OBJECTIVES: To investigate the association between CLBP and sleep disorders, with a focus on the potential role of sleep disorders as a risk factor for CLBP. STUDY DESIGN: Cross-sectional study based on publicly available data from the National Health and Nutrition Examination Survey (NHANES) for one cycle (2009-2010). SETTING: The NHANES employs a complex, multistage probability sampling design to select a nationally representative sample. METHODS: In this study, we included patients aged 20 to 69 years from the NHANES 2009-2010 cycle. After eliminating cases with missing data, a total of 863 patients remained. Baseline characteristics were analyzed by stratifying patients based on their CLBP status to assess initial inter-group disparities. Due to age imbalances between groups, we employed a 1:1 propensity score matching (PSM) method, reducing the sample to 508 patients. The association between CLBP and trouble sleeping was investigated following this calibration using a multivariate logistic regression analysis. RESULTS: Upon categorizing the baseline characteristics of 863 patients based on CLBP, we identified that those within the CLBP group tended to be older and had a greater prevalence of health conditions, including cancer, hypertension, and cardiovascular disease (CVD). Notably, the prevalence of sleep disorders was higher in the CLBP group than in the non-CLBP group (P < 0.001). After implementing an age-based PSM for the 2 groups, 508 patients were selected from the initial 863 patients. After adjusting for various confounders using multivariate logistic regression, our analysis revealed a strong association between sleep disorders and an increased risk of CLBP. LIMITATIONS: This is a cross-sectional study, and therefore causality cannot be established. CONCLUSIONS: This study underscores the significant association between sleep disorders and an elevated risk of CLBP, highlighting the need for comprehensive management strategies that consider the role of sleep disorders in CLBP.

A high resolution and wide range valve for micronewton cold gas thrusters.

Numerous scientific satellites require micronewton thrusters for compensating environmental disturbances. The mass flow control proportional valve plays a crucial role in precisely regulating the thrust. To meet the high resolution and wide range requirements of the thrusters, this paper introduces a novel proportional valve with two sets of independently controllable piezoelectric stack. One set of the piezo-stack is used to compensate the stroke loss of the valve core, mainly caused by the deformation of the valve seat. The valve sealing mechanism is carefully analyzed to reduce the stroke loss. Another set of the stack works as the primary actuator, enabling the high mass flow control resolution. Two sets of independently controlled piezoelectric stacks not only expand the range and improve the range ratio but also provide redundancy and enhance reliability. This means that the actuator can still operate at lower ranges even if one piezo-stack is damaged. The piezo-actuators are assembled using U-shaped connectors, creating a compact and space-efficient overall design. Experimental tests have been conducted to verify the performance of the valve, which demonstrated a mass flow range of 0-675 µg/s with a resolution better than 0.1 µg/s and a flow noise below 0.1 µg/s/Hz1/2 at 0.1 mHz-1 Hz.

Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.

The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.

Tongxinluo Activates PI3K/AKT Signaling Pathway to Inhibit Endothelial Mesenchymal Transition and Attenuate Myocardial Fibrosis after Ischemia-Reperfusion in Mice.

OBJECTIVE: To investigate the potential role of Tongxinluo (TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury (MIRI) in mice. METHODS: A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups (n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril (BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition (EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), α-smoth muscle actin (α-SMA), phosphatidylinositol-3-kinase (PI3K) and phospho protein kinase B (p-AKT) were assessed using Western blot. RESULTS: TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT (P<0.05 or P<0.01). TXL significantly increased the protein expressions of PI3K and p-AKT (P<0.05 or P<0.01). There was no significant difference between TXL and BNPL group (P>0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL. CONCLUSION: TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice.

[Platelet Count Doubling after One Course of Demethylated Drug Therapeutic Predicts the Treatment Response and Efficacy of Patients with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the predictive value of platelet doubling (platelet count doubling) after one course of hypomethylating agents (HMA) on the treatment response and efficacy of myelodysplastic syndrome (MDS). METHODS: Clinical and pathological data of 75 patients who received HMA in our hospital from January 2017 to March 2022 were collected and analyzed. All patients were divided into two groups according to whether their platelet count doubled after one course of treatment, including platelet doubling group and non-doubling group, and statistical analysis was performed to compare the treatment response and efficacy between the two groups. In addition, platelet count changes were compared between azacitidine and decitabine therapy. RESULTS: Compared with the non-doubling platelet count group, the ORR of the doubling platelet group was significantly better after 3 courses of treatment (P =0.002), and there was a statistically significant difference in the number of HI between the two groups (P =0.005). In addition, the median survival time (MST) was 26 months in the platelet doubling group and 11 months in the non-doubling group (P =0.001). The overall survival (OS) and 1- and 2-year survival rates of the platelet doubling group were also significantly better than those of the non-doubing group. Multivariate COX analysis showed that platelet count doubling was an independent predictor of OS in MDS patients after 1 course of treatment (P =0.013). There was no significant difference in the response rate of platelet count doubling between MDS patients treated with azacitidine and decitabine (33.3% vs 23.8%, P >0.05). CONCLUSION: Platelet count doubling after one course of treatment can be used as a predictor of response rate and survival of demethylated drug therapy in MDS patients. In addition, there was no significant difference in the response rate of platelets in MDS patients treated with azacitidine or dicetabine.

A mucus production programme promotes classical pancreatic ductal adenocarcinoma.

OBJECTIVE: The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. DESIGN: We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. RESULTS: Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1ß that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation. CONCLUSIONS: Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.

Leading limb biomechanical response following compelled forward and descending body shift in old versus young adults.

BACKGROUND: Falls pose a significant health risk in older adults, with stair descent falls carrying particularly severe consequences. Reduced balance control and limb support due to aging-related physiological and neuromuscular decline are critical components in increased falling risk in older adults. Understanding the age-associated abnormalities in balance control and limb support strategies during sudden forward and downward body shift could reveal potential biomechanical deficits responsible for increased falling risks in older adults. This study investigates balance regulatory responses following first-time exposure to compelled forward and downward body shift in young and older adults. METHODS: Thirteen healthy old and thirteen healthy young adults participated in this study. Participants stood on two adjacent perturbation platforms in modified tandem stance. The leading limb support surface dropped 3 in. vertically at an unknown time. The anterior margin of stability and center of mass velocity, peak vertical ground reaction forces, and leading limb ankle and knee joint angular displacement, torque, and power during the initial response phase were compared between age groups. FINDINGS: Compared to young adults, older adults showed higher center of mass velocity, lower margin of stability, peak vertical ground reaction force, peak ankle and knee joint power, and peak knee joint torque during the initial response phase. INTERPRETATIONS: The abnormalities potentially identified in our study, particularly in dynamic stability regulation, limb support force generation, and shock absorption may affect the ability to arrest the body's forward and downward motion. These deficits may contribute to an increased risk of forward falls in aging.